Submissions for variant NM_000352.6(ABCC8):c.1501G>A (p.Glu501Lys)

gnomAD frequency: 0.00002  dbSNP: rs372307320

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000674549	SCV000799904	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2018-05-10	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383752	SCV001583007	pathogenic	not provided	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 501 of the ABCC8 protein (p.Glu501Lys). This variant is present in population databases (rs372307320, gnomAD 0.008%). This missense change has been observed in individual(s) with autosomal recessive diffuse or focal hyperinsulinism (PMID: 16357843, 24434300, 31218401). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant has been reported in individual(s) with autosomal dominant hyperinsulinism (PMID: 31218401); however, the role of the variant in this condition is currently unclear. ClinVar contains an entry for this variant (Variation ID: 558304). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 17575084). For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001383752	SCV002067382	pathogenic	not provided	2019-09-10	criteria provided, single submitter	clinical testing
3billion	RCV000674549	SCV002573387	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2022-09-01	criteria provided, single submitter	clinical testing	This missense variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.96). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000558304). The homozygous variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 24434300, 28442472, 31218401). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509505	SCV002819429	pathogenic	Familial hyperinsulinism	2022-12-11	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1501G>A (p.Glu501Lys) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250814 control chromosomes. c.1501G>A has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism predominantly with a diffuse histology (example, Su_2014, Snider_2013, Gong_2016, Li_2017, Wang_2017, Stanley_2014, Ni_2019, Atapattu_2017). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Yan_2007). The most pronounced variant effect results in reduced cell surface expression. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000674549	SCV004026563	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Glu501Lys variant in ABCC8 has been previously reported in 7 individuals with hyperinsulinemic hypoglycemia (PMID: 29082728, 25639667, 15562009, 28442472, 23275527), and has been seen in 0.008% (2/24924) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs372307320). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 558304) and has been interpreted as likely pathogenic/pathogenic by Counsyl, Genetic Services Laboratory (University of Chicago), Invitae, 3billion, and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Of the 7 affected individuals, 2 were compound heterozygotes that carried a pathogenic/likely pathogenic variant in trans, which increases the likelihood that the p.Glu501Lys variant is pathogenic (PMID: 28442472, 23275527). In vitro functional studies provide some evidence that the p.Glu501Lys variant may slightly impact protein function (PMID: 17575084). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PP3, PM2_supporting, PS3_supporting (Richards 2015).
Baylor Genetics	RCV003465538	SCV004199950	likely pathogenic	Type 2 diabetes mellitus	2024-03-30	criteria provided, single submitter	clinical testing